Structural characterisation of the catalytic domain of botulinum neurotoxin X - high activity and unique substrate specificity
Year: 2018
Type: article
Abstract: Botulinum neurotoxins (BoNTs) are among the most potent toxins known and are also used to treat an increasing number of medical disorders. There are seven well-established serotypes (BoNT/A-G), which all act as zinc-dependent endopeptidases targeting specific members of the SNARE proteins required for synaptic vesicle exocytosis in neurons. A new toxin serotype, BoNT/X, was recently identified. It cleaves not only the canonical targets, vesicle associated membrane proteins (VAMP) 1/2/3 at a unique site, but also has the unique ability to cleave VAMP4/5 and Ykt6. Here we report the 1.35 Å X-ray crystal structure of the light chain of BoNT/X (LC/X). LC/X shares the core fold common to all other BoNTs, demonstrating that LC/X is a bona fide member of BoNT-LCs. We found that access to the catalytic pocket of LC/X is more restricted, and the regions lining the catalytic pocket are not conserved compared to other BoNTs. Kinetic studies revealed that LC/X cleaves VAMP1 with a ten times higher efficiency than BoNT/B and the tetanus neurotoxin. The structural information provides a molecular basis to understand the convergence/divergence between BoNT/X and other BoNTs, to develop effective LC inhibitors, and to engineer new scientific tools and therapeutic toxins targeting distinct SNARE proteins in cells.
Source: Scientific Reports
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,477
Funders: Burroughs Wellcome Fund, Wenner-Gren Foundation, Diamond Light Source, Cancerfonden, Vetenskapsrådet, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Harvard Digestive Diseases Center, Harvard University, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1721990140, G332990701, Structural and biophysical studies of the Botulinum neurotoxins, deadly toxins that also can heal., G5857948765, Molecular basis of action and pathogenesis of Clostridium difficile toxin B, Intellectual and Developmental Disablities Research Center, Integrated Epithelial and Muscosal Biology, Biology and Engineering of Botulinum Neurotoxins.
OpenAlex ID: W2793367962